Biology:NLRP3

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Short description: Human protein and coding gene


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 [NALP3] and cryopyrin), is a protein that in humans is encoded by the NLRP3 gene[1] located on the long arm of chromosome 1.[2]

NLRP3 is expressed predominantly in macrophages and as a component of the inflammasome,[3][4]:436 detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NLRP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.

Nomenclature

NACHT, LRR, and PYD are respectively acronyms for:

  • NACHT – NAIP (neuronal apoptosis inhibitor protein), C2TA [class 2 transcription activator, of the MHC, HET-E (heterokaryon incompatibility) and TP1 (telomerase-associated protein 1)
  • LRR – "leucine-rich repeat" [5][6] and is synonymous with NLR, for or nucleotide-binding domain, leucine-rich repeat"[7]
  • PYD – "PYRIN domain," after the pyrin proteins[8] The NLRP3 gene name abbreviates "NLR family, pyrin domain containing 3," where NLR refers to "nucleotide-binding domain, leucine-rich repeat."[7]

The NACHT, LRR and PYD domains-containing protein 3 is also called:

  • cold induced autoinflammatory syndrome 1 (CIAS1),
  • caterpiller-like receptor 1.1 (CLR1.1), and
  • PYRIN-containing APAF1-like protein 1 (PYPAF1).[9]

Structure

This gene encodes a pyrin-like protein which contains a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with pyrin domain (PYD) of apoptosis-associated speck-like protein containing a CARD (ASC). Proteins which contain the caspase recruitment domain, CARD, have been shown to be involved in inflammation and immune response.[1]

Function

NLRP3 is a component of the innate immune system that functions as a pattern recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs).[10] NLRP3 belongs to the NOD-like receptor (NLR) subfamily of PRRs and NLRP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NLRP3 inflammasome. NLRP3 in the absence of activating signal is kept in an inactive state complexed with HSP90 and SGT1 in the cytoplasm. NLRP3 inflammasome detects danger signals such as crystalline uric acid and extracellular ATP released by damaged cells. These signals release HSP90 and SGT1 from and recruit ASC protein and caspase-1 to the inflammasome complex. Caspase-1 within the activated NLRP3 inflammasome complex in turn activates the inflammatory cytokine, IL-1β.[10]

The NLRP3 inflammasome appears to be activated by changes in intracellular potassium caused by potassium efflux from mechanosensitive ion channels located in the cell membrane.[11] It appears that NLRP3 is also regulated by reactive oxygen species (ROS), though the precise mechanisms of such regulation has not been determined.[12]

It is suggested that NLRP3 provides protection against Streptococcus pneumoniae infections by activating STAT6 and SPDEF.[13]

Pathology

Mutations in the NLRP3 gene have been associated with a spectrum of dominantly inherited autoinflammatory diseases called cryopyrin-associated periodic syndrome (CAPS). This includes familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal onset multisystem inflammatory disease (NOMID), and keratoendotheliitis fugax hereditaria.[1][14]

Defects in this gene have also been linked to familial Mediterranean fever.[15] In addition, the NLRP3 inflammasome has a role in the pathogenesis of gout,[10] hemorrhagic stroke[16] and neuroinflammation occurring in protein-misfolding diseases, such as Alzheimer's, Parkinson's, and prion diseases.[17][18][19] Amelioration of mouse models of many diseases has been shown to occur by deletion of the NLRP3 inflammasome, including gout, type 2 diabetes, multiple sclerosis, Alzheimer's disease, and atherosclerosis.[20] The compound β-Hydroxybutyrate has been shown to block NLRP3 activation, and thus may be of benefit for many of these diseases.[21]

Deregulation of NLRP3 has been connected with carcinogenesis. For example, all the components of the NLRP3 inflammasome are downregulated or completely lost in human hepatocellular carcinoma.[22]

Inhibition

The NLRP3 inflammasome has garnered attention as a potential drug target for a variety of diseases underpinned by inflammation. The diarylsulfonylurea MCC-950 has been identified as a potent and selective NLRP3 inhibitor.[23] Nodthera and Inflazome, have entered phase I clinical trials with NLRP3 inhibitors. Another NLRP3 antagonist is Dapansutrile (OLT1177). This β-sulfonyl nitrile molecule compound was developed by Olactec Therapeutics, and is a selective NLRP3 inhibitor. Dapansutrile, been used in clinical trials as a remedy for heart failure, osteoarthritis and gouty arthritis.[24]

References and notes

  1. ↑ 1.0 1.1 1.2 Anon. (2015). "Entrez Gene: NLRP3 NLR family, pyrin domain containing 3 [Homo sapiens (human), Gene ID: 114548 (updated on 13-Nov-2015)"]. Bethesda, MD, USA: National Center for Biotechnology Information, National Library of Medicine. https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=114548. 
  2. ↑ "Identification of a locus on chromosome 1q44 for familial cold urticaria". American Journal of Human Genetics 66 (5): 1693–8. May 2000. doi:10.1086/302874. PMID 10741953. 
  3. ↑ "P2X7R: a potential key regulator of acute gouty arthritis". Seminars in Arthritis and Rheumatism 43 (3): 376–80. Dec 2013. doi:10.1016/j.semarthrit.2013.04.007. PMID 23786870. 
  4. ↑ "Structural mechanisms of inflammasome assembly". The FEBS Journal 282 (3): 435–44. Feb 2015. doi:10.1111/febs.13133. PMID 25354325. 
  5. ↑ "The NACHT family - a new group of predicted NTPases implicated in apoptosis and MHC transcription activation". Trends in Biochemical Sciences 25 (5): 223–4. May 2000. doi:10.1016/S0968-0004(00)01577-2. PMID 10782090. 
  6. ↑ "Carcinoid syndrome treated by hepatic embolization". AJR. American Journal of Roentgenology 131 (3): 511–3. Sep 1978. doi:10.2214/ajr.131.3.511. PMID 99001. 
  7. ↑ 7.0 7.1 "Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases". Journal of Immunology 183 (12): 7623–9. Dec 2009. doi:10.4049/jimmunol.0902425. PMID 20007570. 
  8. ↑ "The PYRIN domain: a novel motif found in apoptosis and inflammation proteins". Cell Death and Differentiation 7 (12): 1273–4. Dec 2000. doi:10.1038/sj.cdd.4400774. PMID 11270363. 
  9. ↑ Q96P20
  10. ↑ 10.0 10.1 10.2 "Detection of immune danger signals by NALP3". Journal of Leukocyte Biology 83 (3): 507–11. Mar 2008. doi:10.1189/jlb.0607362. PMID 17982111. 
  11. ↑ "Activation of NLRP3 inflammasome by crystalline structures via cell surface contact". Scientific Reports 4: 7281. 2014. doi:10.1038/srep07281. PMID 25445147. Bibcode: 2014NatSR...4E7281H. 
  12. ↑ "Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments". Current Opinion in Immunology 25 (1): 40–45. Feb 2013. doi:10.1016/j.coi.2012.12.004. PMID 23305783. 
  13. ↑ "ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism". Mucosal Immunology 12 (5): 1092–1103. September 2019. doi:10.1038/s41385-019-0181-1. PMID 31278375. 
  14. ↑ "Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene". American Journal of Ophthalmology 184: 41–50. Jan 2018. doi:10.1016/j.ajo.2018.01.017. PMID 29366613. 
  15. ↑ "Primer: inflammasomes and interleukin 1beta in inflammatory disorders". Nature Clinical Practice Rheumatology 4 (1): 34–42. Jan 2008. doi:10.1038/ncprheum0681. PMID 18172447. 
  16. ↑ "Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update". J Cereb Blood Flow Metab 40 (9): 1752–1768. May 2020. doi:10.1177/0271678X20923551. PMID 32423330. 
  17. ↑ "Intracellular innate immunity in gouty arthritis: role of NALP3 inflammasome". Immunology and Cell Biology 88 (1): 20–3. Jan 2010. doi:10.1038/icb.2009.93. PMID 19935768. 
  18. ↑ "NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice". Nature 493 (7434): 674–8. Jan 2013. doi:10.1038/nature11729. PMID 23254930. Bibcode: 2013Natur.493..674H. 
  19. ↑ "NALP3 inflammasome activation in protein misfolding diseases". Life Sciences 135: 9–14. Aug 2015. doi:10.1016/j.lfs.2015.05.011. PMID 26037399. 
  20. ↑ "Taming the inflammasome". Nature Medicine 21 (3): 213–215. 2015. doi:10.1038/nm.3808. PMID 25742454. https://www.weizmann.ac.il/immunology/elinav/sites/immunology.elinav/files/nm_newsviews_2015.pdf. 
  21. ↑ "The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease". Nature Medicine 21 (3): 263–269. 2015. doi:10.1038/nm.3804. PMID 25686106. 
  22. ↑ "Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression". Laboratory Investigation 94 (1): 52–62. Jan 2014. doi:10.1038/labinvest.2013.126. PMID 24166187. 
  23. ↑ "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases". Nature Medicine 21 (3): 248–55. March 2015. doi:10.1038/nm.3806. PMID 25686105. 
  24. ↑ Alzheimer's Drug Discovery Foundation., Dapansutrile.. "Dapansutrile". https://www.alzdiscovery.org/uploads/cognitive_vitality_media/Dapansutrile-Cognitive-Vitality-For-Researchers.pdf. 

External links

  • Overview of all the structural information available in the PDB for UniProt: Q96P20 (NACHT, LRR and PYD domains-containing protein 3) at the PDBe-KB.



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